title: Lipopolysaccharide stimulates platelets through an IL-1β autocrine loop.
abstract: LPS activates platelets through TLR4, aiding productive sepsis, with stimulated splicing and translation of stored heteronuclear pro-IL-1β RNA. Although the IL-1R type 1 (IL-1R1) receptor for IL-1 shares downstream components with the TLR4 receptor, platelets are not known to express IL-1R1, nor are they known to respond to this cytokine. We show by flow cytometry and Western blotting that platelets express IL-1R1, and that IL-1β and IL-1α stimulate heteronuclear I-1β splicing and translation of the newly made mRNA in platelets. Platelets also respond to the IL-1β they make, which is exclusively associated with shed microparticles. Specific blockade of IL-1R1 with IL-1R antagonist suppressed platelet stimulation by IL-1, so IL-1β stimulates its own synthesis in an autocrine signaling loop. Strikingly, IL-1R antagonist inhibition, pharmacologic or genetic suppression of pro-IL-1β processing to active cytokine by caspase-1, or blockade of de novo protein synthesis also blocked LPS-induced IL-1β mRNA production. Robust stimulation of platelets by LPS therefore also required IL-1β amplification. Activated platelets made IL-1β in vivo as IL-1β rapidly accumulated in occluded murine carotid arteries by posttranscriptional RNA splicing unique to platelets. We conclude that IL-1β is a platelet agonist, that IL-1β acts through an autocrine stimulatory loop, that an IL-1β autocrine loop is required to amplify platelet activation by LPS, and that platelets immobilized in occlusive thrombi are activated over time to produce IL-1β. IL-1 is a new platelet agonist that promotes its own synthesis, connecting thrombosis with immunity.
authors.affiliation: Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio.|Cell Biology Graduate Training Program, Medical Scientist Training Program, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: G Thomas
authors.initials: GT
authors.lastname: Brown
authors.affiliation: Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio.
authors.forename: Padmini
authors.initials: P
authors.lastname: Narayanan
authors.affiliation: Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio.
authors.forename: Roy L
authors.initials: RL
authors.lastname: Silverstein
authors.affiliation: Department of Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio.|Cell Biology Graduate Training Program, Medical Scientist Training Program, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: McIntyre
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000276:immunology* / Q000378:metabolism; D020170:Caspase 1; D002478:Cells, Cultured; D006801:Humans; D007249:Inflammation / Q000276:immunology; D053582:Interleukin-1alpha / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism*; D051379:Mice; D015539:Platelet Activation / Q000276:immunology*; D012326:RNA Splicing; D012333:RNA, Messenger; D053573:Receptors, Interleukin-1 Type I / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015398:Signal Transduction; D013927:Thrombosis / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D053573:Receptors, Interleukin-1 Type I; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D020170:Caspase 1